Injector for fluid delivery system

ABSTRACT

An injector for a fluid delivery system is provided to deliver precise volumes of a plurality of fluids in sequence to a treatment reservoir. The injector is in fluid communication with a positive displacement pump which accepts fluid from a fluid source. The injector includes a spring loaded plunger, an end of which contacts a diaphragm adapted to seal an injector inlet from an injector outlet. The end of the plunger is shaped to seat the diaphragm against the injector outlet and to position the diaphragm away from the injector inlet.

BACKGROUND OF THE INVENTION

This invention relates to an injector component of the fluid deliverysystem.

Prior to the present invention, fluid delivery systems have beenavailable which minimize system volume and which minimize intermixing offluids while delivering a precise amount of a fluid for chemicalreaction. These systems are generally utilized for chemical processesinvolving a large number of sequentially effected chemical reactionssuch as in protein synthesis, deoxyribo- nucleic acid (DNA) synthesis orwhen sequencing proteins.

U.S. Pat. No. 4,008,736 discloses a valve block containing a capillaryformed of capillary segments bored at about 30° from a contact surfaceof the block. The junctions of the capillary segments are effected atthe contact surface and within the block. The junctions at the contactsurfaces form valving sites to which are engaged apertured slidingblocks which effect fluid communication with the capillary. While thesliding blocks are effective in providing the desired fluid flow, theywear rapidly thereby causing undesirable leaks.

U.S. Pat. No. 4,168,724 discloses a similar device but replaces theslider valves with diaphragm check valves. The fluid is deliveredthrough the valves from a pressurized fluid storage source. This systemis undesirable because The type of diaphragm valve used is undesirablysusceptible to particulate contamination. In addition, the pressure dropthrough the valves is difficult to control which causes inaccuratereagent delivery.

U.S. Pat. No. 4,558,845 discloses a fluid delivery system utilizing avalve block assembly comprising a separate block for each valve site.The common conduit to the reaction site is alternately a channel in ablock and tubing connecting two adjacent blocks. This arrangementrequires a plurality of fittings which are subject to leaking.

U.S. Pat. No. 4,773,446 discloses a valve block assembly which utilizesdiaphragm valves. The valves serve to control fluid flow from aplurality of pressurized fluid reservoirs, in sequence to a commonoutlet reservoir. This system requires the use of conduits from thefluid reservoirs and fittings to valve blocks for each conduit. Thefittings are subject to leakage.

The fluid delivery system of the prior art depend upon the use ofpositive pressure to deliver the fluid and upon the control of backpressure to the fluid reservoir in order to precisely control the amountof fluid delivered to a treatment reservoir. These systems require thefrequent adjustment of the fluid delivery means as a function of backpressure. These systems deliver fluids against back pressures only up toabout 10 psig. It would be desirable to provide a system whicheliminates the need of adjustment of the fluid delivery means. It wouldalso be desirable to deliver fluids in a way that is independent of backpressure. Accurate delivery of reagent improves performance and reducesreagent consumption.

It would also be desirable to provide a fluid delivery system whichminimizes the use of tubes and tube fittings while minimizing the volumeof the system as compared to Presently available systems.

SUMMARY OF THE INVENTION

The present invention provides an injector component for a fluiddelivery system for delivering a plurality of fluids in sequence to atreatment reservoir wherein a chemical reaction or a physical treatmentstep occurs. Channels are formed in a solid plate to which is laminateda sealing layer in order to seal the channels. The surface of the solidplate opposite the surface to which the sealing layer is laminatedcontains the fluid connections for the means for delivering fluids. Thefluids are delivered to a desired point by means of a system comprisinga diaphragm check valve, a diaphragm pump and the injector, each indirect fluid communication with the channels in the solid plate. Theinjector provides or prevents fluid communication between an inletchannel and an outlet channel. Transfer of fluid between the check valveand the injector is effected by the pump. A common outlet channel isconnected to sources of a plurality of fluids emanating from theinjector(s) and a switching means which directs fluid to a desireddestination such as a reaction column. The switching means has thecapacity to direct one or two sets of fluids to one or two desireddestinations. Used fluid then is removed from the desired destination towaste.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a system useful for producing DNA.

FIG. 2 is a cross-sectional view of a check valve-pump-injector valveunit incorporating the injector of this invention.

FIG. 3 is a top view of an apparatus utilizing the injector of thisinvention, useful for implementing the system of FIG. 1.

FIG. 4 is a side, cross sectional view of a means for attaching a fluidreservior to a check valve utilized with this invention.

FIG. 4 A is an exploded view of elements forming the check valve of FIG.4.

FIG. 5 is a side view, in partial cross section of a partition valveutilized with the injector of this invention.

FIG. 6 is an exploded view of the elements forming the partition valveof FIG. 5.

FIG. 7 is an exploded isometric view of the elements forming thepartition valve of FIG. 5.

DESCRIPTION OF SPECIFIC EMBODIMENTS

In accordance with this invention, an injector is utilized with a fluiddelivery system having a plate with channels for effecting fluid passagethrough the channel. The system is constructed to effect passage of aplurality of fluids in sequence through the system to at least onetreatment reservoir. The means for transporting each fluid comprises acheck valve, a positive displacement diaphragm pump and the injector ofthis invention. The check valve is connected to a source of fluid and isin direct fluid communication with the diaphragm pump. The diaphragmpump is directly connected to the injector and functions to transportfluid from the check valve to and through the injector. Each injector ofthis invention is in fluid communication with a common passageway whichconnects with a treatment reservoir where chemical reaction or physicalfluid manipulation is effected. The system utilizing the injector ofthis invention is particularly suitable for use in processes wheresequential chemical reactions are conducted under carefully controlledconditions. Examples of such processes include nucleic acid or proteinsynthesis and protein sequencing. These processes require sequentialchemical reactions which are alternated with washing steps to removeexcess unreacted reagent. In some instances, the reagents require aparticular atmospheric environment such as an inert environment or anoxidizing environment. In these instances, gases are provided to thefluid reservoir. Therefore, these processes require fluid deliverysystems wherein reagent, processing chemicals and gases are processed ina precise manner so that precise volumes of fluid are delivered to theappropriate destination within the system at the proper time and withinthe proper sequence. When a plurality of treatment reservoirs areutilized, switching means are provided to direct the appropriatereagent, process chemical or gas to the appropriate treatment reservoir.

The check valve, diaphragm pump and injector are utilized in conjunctionwith each other to deliver a precise volume of fluid from a fluidreservoir to a treatment reservoir. Suitable control means such ascomputer control are provided to control the sequence of fluidsdelivered to the treatment reservoir or reservoirs.

The plate containing the channels for fluid flow is conveniently formedof a ceramic material which can be photoetched to form the channelsystem in the desired configuration. A surface of the plate contains thechannels while the opposing surface of the plate includes the fluidinlets and outlets through which fluid flow is controlled. The surfaceof the plate including the channels is sealed to a bottom plate membersuch as glass or plastic. Sealing is effected to seal the channels intothe desired flow configuration. The bottom plate member provides theadvantage of a direct view to the channel system so that abberations inthe system can be observed readily.

The diaphragm pump is a positive displacement pump secured to the platetogether with the check valve and the injector. The diaphragm pump canprecede the check valve or follow the check valve along the path offluid flow to the injector. A diaphragm is positioned between a sourceof fluid pressure for driving the diaphragm and a cavity within whichthe diaphragm can move. Fluid from a fluid source is passed through thecheck valve and a channel in the plate to fill the cavity in thediaphragm pump. When pressure is increased within the pump, thediaphragm is forced into the pump cavity (plenum) and directs to theinjector an amount of fluid equal to the volume of the plenum. The pumpcavity (plenum) is contoured so that the diaphragm completely purges allfluid from the pump cavity with each pulse of the diaphragm. The shapeof the cavity, e.g., spherical, also prevents the diaphragm materialfrom being stretched beyond its elastic limit. The fluid, directed tothe injector under pressure, forces the diaphragm in the injector toopen thereby to effect fluid communication between the injector inletand the injector outlet and to force fluid from the injector to thetreatment reservoir.

The injector of this invention includes a housing secured to the plateand a spring-loaded plunger within the housing which is biased towardthe plate. An injector diaphragm is positioned between (a) the plungerand (b) the injector inlet and injector outlet on the plate. The end ofthe plunger is shaped so as to seat the diaphragm against the injectoroutlet and away from the injector inlet. The area of the diaphragmexposed to the inlet pressure is larger than the area exposed to theoutlet pressure. This ratio of exposed areas, for a given pumpingpressure provides an increased area at the inlet as compared to the areaat the outlet so that the plunger is more easily lifted by pressureapplied through the inlet as compared to pressure applied at the outlet.Generally, the ratio of the inlet area to the outlet area is betweenabout 2:1 and about 3:1. The system utilizing the injector of theinvention will be described with reference to a process for producingpolymeric nucleic acids (NA). Referring to FIG. 1 a process for makingNA is shown schematically. The process shown utilizes two sets of fluidreagents with one set in fluid communication with common channel 10 anda second set in fluid communication with common channel 12. The firstset includes a gas blow-through means for purging the system (Gas B)connected to channel 13, acetonitrile connected to channel 14, tetrazole(TET) connected to channel 15, an auzilliary reservoir (AUX) connectedto channel 16, adenosine connected to channel 17, cytidine connected tochannel 18, guanosine connected to channel 19 and thymidine connected tochannel 20. The second set of fluids include a gas blow-through meansfor purging the system (GAS-A) connected to channel 21, acetonitrileconnected to channel 22, capping solution A (CAP-A) connected to channel23, capping solution B (CAP-B) connected to channel 24, oxidizer (OXID)connected to channel 25, diochloroacetic acid solution (DCA) connectedto channel 26 and auxiliary reservoir (AUX) connected to channel 27. Thereagents, adenosine, cytidine, guanosine and thymidine are reaqents usedto form the DNA as is well known in the art. GAS-A and Gas-B provide thefunction of purging the system and transporting small volumes of liquidout of the sustem to a detector. Acetonitrile provides the function ofrinsing the system. Acetic anhydride (CAP-A) and N-methylimidazole(CAP-B) provide the function of terminating unreacted sites to preventfurther elongation of the failure sequences. OXID provides the functionsuch as iodine in water/pyridine and tetrahydrofuran mixture ofoxidizing the elongated chain to stabilize the internucleotide phosphatelinkages. DCA provides the function of AUX provides the function ofdeprotecting the bound residue to permit further condensation reaction.TET provides the function of activating the reactive monomer for thenext coupling. Partition valve 28 serves as a switch to direct fluidfrom either channel 10 or channel 12 to either treatment reservoir 29comprising a reaction column containing a solid support such ascontrolled pore glass (CPG) or a membrane through channel 31 ortreatment column 30 which is a duplicate of column 29 through channel32. Channels 33 and 34 direct processed fluid to waste.

Referring to FIG. 2, the fluid delivery system of this invention isshown. The fluid delivery system comprises the check valve of thisinvention 35, a diaphragm pump 36 and an injector 37. The check valve 35includes housing 38 to which a fitting is attached to accomodate aconnection to a fluid reservoir. A top insert 40 includes a cavity 41housing a filtration means 84. A bottom insert 42 includes a plenum 43and a check valve outlet 44. A diaphragm 45 is secured between topinsert 40 and bottom insert 42. Check valve outlet 44 communicates withchannel 46 formed within plate 47. Channel 46 is sealed by a secondplate 48 which is preferably transparent. Diaphragm pump 36 comprises aspring 11, a top insert member 49 and a bottom insert member 50 betweenwhich is secured diaphragm 51. The inserts 49 and 50 are crimpedtogether and are positioned within housing 52. Channel 46 communicateswith pump inlet 53 which, in turn, communicates with pump plenum 54.Insert 49 contains a cavity 57 to connect to a fluid source which can beopened or closed to alternately apply or remove pressure on the topsurface of the diaphragm 51. Pump outlet 53 communicates with channel 55which communicates with injector inlet 56. Injector 37 includes aplunger 58, an injector diaphragm 59 and injector outlet 60. The end 61of the plunger 58 is shaped so that the diaphragm 59 seats againstoutlet 60 and is positioned away from inlet 56. In use, pressure isapplied to the fluid within fluid outlet 39 for example about 5 to 10psig while pressure is reduced within cavity 57. Diaphragm 45 isexpanded under pressure, away from inlet 41 and fluid is expelled intooutlet 44, channel 46, pump inlet 53 to fill plenum 54 which has aknown, fixed volume. When it is desired to expel fluid from cavity 54,high pressure in cavity 57 is effected which causes diaphragm 45 incheck valve 35 to close and to cause plunger 58 to be raised anddiaphragm 61 to open in injector 37. The pressurized fluid is directedthrough injector outlet 60. After, the volume of fluid in cavity 54 hasbeen expelled through injector outlet 60, pressure at injector inlet 56is reduced and plunger 58 returns to the position shown in FIG. 2wherein access from injector inlet 56 to injector outlet 60 is closed.

A function of the system of this invention is described with referenceto FIG. 3 and a process for producing DNA. The reactants adenosine,cytidine, guanosine and thymidine are housed in containers 17, 18, 19and 20 respectively. The system of check valve 35, diaphragm pump 36 andinjector 37 functions to direct adenosine to channel 12 in plate 47.Duplicate systems of a check valve, a diaphragm pump and injector areutilized for the remaining reactants and are not described in detailherein so as to reduce duplication. All of these reactants however, passfrom their respective storage containers into channel 12. From channel12, the reagents pass sequentially to partition switch 28 where they aredirected through conduit 31 to reaction column 29 or through conduit 32to reaction column 30. Subsequent to reaction, the excess reagent passesto waste either through channel 33 or channel 34. Pressurized blanketgas is directed from a container (not shown) attached to and in fluidcommunication with connector 70a and is directed through channel 70, 71and 72 to containers 14 and 15 as well as through channel 73 tocontainers 16, 17, 18, 19 and 20. Sufficient pressure from the blanketgas is applied to open the check valves when the associated diaphragmpumps are not actuated. Similarly, blanket gas is supplied from acontainer (not shown) through connector 74 through channel 75 tocontainers 23, 24 and 25. DCA and ACN-A are pressurized by a separatesystem (not shown). Blow-A and Blow-B provide a means to inject highpressure gas into the system for blowing out the two reagent trains.Blow-A and Blow-B enter the system through the same type of injectorvalve as described herein without the need for a pump.

Referring to FIGS. 4 and 4A, the check valve housing utilized in thepresent invention is secured to plate 47 in a manner which will bedescribed with reference to the housing for the partition valve of FIG.7. The check valve 38 includes a reservoir fitting 77 which fits withinhousing 38 and an O-ring and contains a vertical annulus 78 and adelivery tube 79. The end of the delivery tube 79 is secured betweenwasher 80 and top insert 40. The reservoir fitting 77 bears againstwasher 80 by means of a screw thread engagement to port 38 and is sealedby O-ring 81. A fluid reservoir 82 is positioned means 83 and is held inplace by friction. A porous frit filtration element 84 is positionedwithin top insert 40 adjacent diaphragm 45 containing holes.Pressurizing gas for the fluid is introduced through channel 73, pastbottom inlet 42, into zone 86, through opening 87 and into channel 88past tube 79 for entrance into the fluid reservoir 82. As shown in FIG.4A, diaphragm 45 contains four holes which allow fluid passage from thebore 78 into plenum 43 when the diaphragm 45 is not sealed againstinsert 40.

Referring to FIGS. 5, 6 and 7, the partition valve consists of aplurality of elements. As specifically shown in FIG. 7, the ceramicplate includes three layers, 47, 89 and 90. Layer 47 contains channels10, 12, 31 and 32 of partition valve 28. Layer 89 contains a centralopening 94 and peripheral openings 91 into which flanges 92 of housing93 fit. Layer 90 includes slots 95 into which flanges 92 fit. Thehousing 93 is passed through the slots 95 and then rotated so thatflanges 92 are positioned under extensions 101 to retain housing 93 inplace. Prior to positioning the housing 93 in place, the valve body 96is placed into opening 91 of layer 89 and to position partition valvediaphragm 98 over the opening 97 of layer 47. Layer 89 includes opening91 slumped to maintain the angular position of the valve body 96. Aspring 99 is provided to retain the valve body 96 in place withinhousing 93 and effect a fluid seal against the plate. Four tubes (twoshown) 100 are positioned within valve body 96 over the substream inlets102 and the substream outlets 97 in layer 47 which communicates with anytwo of channels 10, 12, 31 and 32 (See FIG. 6). By this arrangement itis possible to control the communication between the substream inlets onand substream outlest 97 to selectively open and close them to effectfluid communication between channels 10 or 12 with channels 31 or 32 byexerting or removing pneumatic pressure through selected tubes 100 onselected areas of diaphragm 98.

I claim:
 1. The system for directing a plurality of fluids in sequenceto a treatment reservoir which comprises at least two fluid reservoirsand a fluid transport means comprising a check valve, a diaphragm pumpand an injector in fluid communication with each of said reservoirs;saidcheck valve having a check valve inlet and a check valve outlet, adiaphragm positioned between said check valve inlet and said check valveoutlet and means for positioning said diaphragm in a position forpreventing fluid communication between said check valve inlet and saidcheck valve outlet and for providing fluid communication between saidcheck valve inlet and said check valve outlet; said diaphragm pumpincluding a Plenum and a pump diaphragm and means for moving said pumpdiaphragm between a position for filling said plenum with fluid and foremptying said plenum of fluid; a plunger positioned within a housing,said plunger being spring biased toward said injector inlet and saidinjector outlet, said housing including means for being secured to aplate having said inlet and said outlet, a diaphragm positioned between(a) said plunger and housing and (b) said injector inlet and injectoroutlet, said plunger having an end adjacent said injector inlet andinjector outlet, means for permitting said plunger to move between afirst position wherein said injector inlet and said injector outlet arein fluid communication and a second position wherein fluid communicationbetween said injector inlet and said injector outlet is prevented, inresponse to fluid pressure, plate means including passageways forproviding fluid communication between said check valve, said diaphragmpump and said injector; and means in said plate for directing fluid fromsaid injector to a treatment reservoir.
 2. The system of claim 1 whereinsaid plunger has a first portion of a surface extending toward saidinjector outlet and a second portion of its surface extending away fromsaid injector inlet.
 3. The system of claim 1 wherein the ratio of theinjector inlet area to the injector outlet area is between about 2:1 andabout 3:1.
 4. The system of claim 2 wherein the ratio of the injectorinlet area to the injector outlet area is between about 2:1 and about3:1.